(a) Field of the Invention
The present invention relates to methods, pharmaceutical compositions, and compounds for enhancing insulin-dependent glucose uptake. The compounds of the invention activate the insulin receptor kinase, leading to an increased sensitivity to insulin and an increase in glucose uptake. The invention relates in particular to the use of the compounds in methods for the treatment of humans with hyperglycemia, and especially for the treatment of Type II diabetes.
(b) Description of Related Art
Among the many functions performed by peptide and protein hormones in metabolism is the ability to interact with receptors with high specificity. The insulin receptor is present on virtually all cells and at high concentrations on the cells for the liver, skeletal muscles, and adipose tissue. Stimulation of the insulin receptor with insulin is an essential element in carbohydrate metabolism and storage.
Diabetics either lack sufficient endogenous secretion of the insulin hormone (Type I) or have an insulin receptor-mediated signaling pathway that is resistant to endogenous or exogenous insulin (Type II, or non-insulin-dependent diabetes mellitus (NIDDM)). Type II diabetes is the most common form of diabetes, affecting about 5% of individuals in the industrialized nations. In Type II diabetics, major insulin-responsive tissues such as liver, skeletal muscle and fat exhibit the insulin resistance (Haring and Mehnert, Diabetologia 36:176-182 (1993); Haring et al., Diabetologia, 37 Suppl 2:S149-54 (1994)). The resistance to insulin in Type II diabetes is complex and likely multifactorial but appears to be caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. Impairment of the insulin receptor kinase has been implicated in the pathogenesis of this signaling defect. Insulin resistance is also found in many non-diabetic individuals, and may be an underlying etiologic factor in the development of the disease (Reaven, Diabetes, 37:1595-1607 (1988)).
Considerable information is known concerning the insulin receptor itself. The receptor consists of four separate subunits consisting of two identical xcex2 and two identical xcex2 chains. The xcex2 subunits contain a tyrosine kinase activity and the ATP binding sites. The insulin receptor is activated by autophosphorylation of key tyrosine residues in its cytoplasmic tyrosine kinase domain. This autophosphorylation is required for subsequent activity of the insulin receptor. The autophosphorylation stabilizes the activated receptor kinase resulting in a phosphorylation cascade involving intracellular signaling proteins.
At present there are limited pharmacologic approaches to treatment of Type II diabetes. Insulin is currently used as a treatment, but is disadvantageous because it must be injected and because its extreme potency requires careful titration of dose. Although several peptide analogs of insulin have been described, none with a molecular weight below about 5000 Daltons retains activity. Some peptides which interact with sites on the xcex2-subunit of the insulin receptor have shown enhancement of the activity of insulin on its receptor (Kole et al., J. Biol Chem., 271:31619-31626 (1996); Kasuya et al., Biochem. Biophys. Res. Commun., 200:777-83 (1994)). Kohanski and others have reported on a variety of polycationic species that generate a basal effect, but do little to enhance insulin action (Kohanski, J. Biol. Chem., 264:20984-91 (1989); Xu et al., Biochemistry 30:11811-19 (1991). These peptides apparently act on the cytoplasmic kinase domain of the insulin receptor.
In addition, certain non-peptide components have been found to enhance the agonist properties of peptide hormones, but none appear to act directly on the insulin receptor kinase. For instance, the ability of thiazolidinediones, such as pioglitazone, to enhance adipocyte differentiation has been described (Kletzien, et al., Mol. Pharmacol., 41:393 (1992)). These thiazolidinediones represent a class of potential anti-diabetic compounds that enhance the response of target tissues to insulin (Kobayashi, Diabetes, 41:476 (1992)). The thiazolidinediones act at an unknown site downstream from the insulin receptor itself and do not have a direct effect on the insulin receptor kinase. Other anti-diabetic agents currently in use include both insulin secretagogues (such as the sulfonylureas) and biguanides (such as metformin) that inhibit hepatic glucose output. To date, non-peptide substances which can mimic the activating effect of insulin on the insulin receptor have eluded discovery.
A variety of polyanionic sulfonic acid derivatives including suramin, azo dyes and related compounds are known in the art and have been established as potential therapeutics for a variety of disease indications. Suramin, described in 1917, is a polysulfonic acid that has been extensively researched (Dressel, J. Chem. Ed., 38:585 (1961); Dressel, J. Chem. Ed., 39:320 (1962)). It has therapeutic uses as an anthelmintic and antiprotozoal. More recently, it has been described as an inhibitor to reverse transcriptase in certain avian and murine retroviruses (De Clercq, Cancer Letters, 8:9 (1979); Mitsuya et al., Science, 226:172 (1984)). Large numbers of compounds relating to suramin exist. Most of the suramin analogs which have been reported have multiple sulfonic acid functionality on each aryl ring. Recent studies indicate that polyanionic suramin analogs have anti-angiogenic, antiproliferative activity, and anti-viral activity (Gagliardi et al., Cancer Chemother. Pharmacol., 41:117 (1988); Doukas et al., Cancer Res., 55: 5161 (1995); Mohan et al., Antiviral Chem., 2:215 (1991)). A number of other bisnaphthylsulfonic acids have been described in the patent literature as complement inhibitors (U.S. Pat. No. 4,132,730, U.S. Pat. No. 4,129,591, U.S. Pat. No. 4,120,891, U.S. Pat. No. 4,102,917, U.S. Pat. No. 4,051,176). Additionally, there are a number of azo dye patents (DE 19521589, U.S. Pat. No. 3,716,368, DE 2216592, FR 1578556) which disclose polysulfonated naphthalene azo compounds. However, none of the suramin analogs or azo dyes have been suggested to be useful in the treatment of hyperglycemia or diabetes.
This invention is directed to pharmaceutical compositions comprising naphthalene sulfonic acids and related compounds which enhance glucose uptake into cells, to the naphthalene sulfonic acids and related compounds, and to methods for enhancing glucose uptake in mammals using these pharmaceutical compositions and compounds.
In one aspect, this invention is directed to pharmaceutical compositions comprising (i) a pharmaceutically acceptable carrier and (ii) as an active ingredient, a compound of formula I: 
where:
R1 and R2 are, independently, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, xe2x80x94C(O)R4, xe2x80x94C(O)OR4, xe2x80x94C(O)NR4R5, xe2x80x94S(O)2R4, xe2x80x94S(O)2OR4, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, aryl(lower)alkyl, substituted aryl(lower)alkyl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, or lower alkenyl, or R1 and R2 together with the conjoining nitrogen are C3-C9 heteroaryl, C3-C5 heterocyclyl, or both R1 and R2 are oxygen and together with the conjoining nitrogen forming xe2x80x94NO2,
R3 is a substituent on the B ring and is xe2x80x94SO2OR6, xe2x80x94C(O)OR6, xe2x80x94SO2NR62, xe2x80x94C(O)NR62 or tetrazolyl;
each R4 and R5 is, independently, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryl(lower)alkyl, substituted aryl(lower)alkyl, substituted heteroaryl, heteroaryl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, heterocyclyl, substituted heterocyclyl, or lower alkenyl,
each R6 and R7 is, independently, hydrogen or lower alkyl,
each R8 is, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl(lower)alkyl, substituted aryl(lower)alkyl, substituted heteroaryl, heteroaryl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, heterocyclyl, substituted heterocyclyl, lower alkenyl, nitro, halo, cyano, xe2x80x94OR9, xe2x80x94SR9, xe2x80x94C(O)R9, xe2x80x94OC(O)R9, xe2x80x94C(O)OR9, xe2x80x94NR92, xe2x80x94C(O)NR92, xe2x80x94NR9C(O)R9, xe2x80x94OSO2R9, xe2x80x94SO2OR9, xe2x80x94SO2NR92, or xe2x80x94NR9SO2R9,
each R9 is, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, heterocyclyl, substituted heterocyclyl, aryl(lower)alkyl, or substituted aryl(lower)alkyl,
R10 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
each linker xe2x80x94WYxe2x80x94 between the naphthyl and phenyl intersects the A ring on the naphthyl and is, independently, xe2x80x94C(O)NR7xe2x80x94, xe2x80x94NR7C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94NR7CH2xe2x80x94, xe2x80x94CH2NR7xe2x80x94, xe2x80x94NR7C(O)NR7xe2x80x94, xe2x80x94NR7C(O)Oxe2x80x94, xe2x80x94OC(O)NR7xe2x80x94, xe2x80x94NR7SO2Oxe2x80x94, xe2x80x94OSO2NR7xe2x80x94, xe2x80x94OC(O)Oxe2x80x94, xe2x80x94SO2NR7xe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94OSO2xe2x80x94, or xe2x80x94SO2Oxe2x80x94,
each Z is a non-interfering substituent, and
each x and v is, independently, 0, 1, 2 or 3,
as a single stereoisomer or mixture of stereoisomers,
or a pharmaceutically acceptable salt thereof.
In a second aspect, the invention provides a method of stimulating the kinase activity of the insulin receptor comprising contacting the insulin receptor, or the kinase portion thereof, with a compound of the first aspect of this invention, in an amount sufficient to stimulate the kinase activity of the insulin receptor.
In a third aspect, this invention provides a method of activating the insulin receptor or enhancing the activation of the insulin receptor by insulin comprising contacting the insulin receptor, or the kinase portion thereof, with a compound of the first aspect of this invention, in an amount sufficient to activate the insulin receptor or enhance insulin""s activation of the insulin receptor. Enhancement of insulin""s ability to activate its receptor in a mammal may be effected by administering the compound of the first aspect of this invention to the mammal.
In a fourth aspect, the invention provides the use of a compound of the first aspect of this invention in a method of stimulating the uptake of glucose into cells which display the insulin receptor. This method of stimulating the uptake of glucose into cells which display the insulin receptor comprises contacting the cells in the presence of insulin with a compound of the first aspect of this invention in an amount sufficient to stimulate the uptake of glucose into the cells. The uptake of glucose into cells in a mammal may be effected by administering the compound of the first aspect of this invention to the mammal.
Other aspects of the invention are directed to the use of a compound of the first aspect of this invention in the treatment of hyperglycemia, type I diabetes, or type II diabetes in a mammal, such as a human. These methods of treatment all comprise the step of administering a therapeutically effective amount of the a compound of the first aspect of this invention to the mammal. Optionally, the methods of treatment may also comprise administering insulin to the mammal.
Another aspect of the invention is directed to compounds of formula I, where: each R4 and R5 is, independently, hydrogen, alkyl, R11-substituted alkyl, aryl, R11-substituted aryl, aryl(lower)alkyl, R11-substituted aryl(lower)alkyl, R11-substituted heteroaryl, heteroaryl, heteroaryl(lower)alkyl, substituted R11-substituted heteroaryl(lower)alkyl, heterocyclyl, R11-substituted heterocyclyl, or lower alkenyl; each R11 is, independently, aryl, substituted aryl, alkyl, substituted alkyl, substituted heteroaryl, heteroaryl, heterocyclyl, substituted heterocyclyl, lower alkenyl, nitro, halo, cyano, xe2x80x94OR12, xe2x80x94SR12, xe2x80x94C(O)R12, xe2x80x94OC(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR122, xe2x80x94C(O)NR132, xe2x80x94NR12C(O)R13, xe2x80x94OSO2R12, xe2x80x94SO2OR12, xe2x80x94SO2NR122, or xe2x80x94NR12SO2R12; and each R12 and R13 is, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, heterocyclyl, substituted heterocyclyl, aryl(lower)alkyl, or substituted aryl(lower)alkyl; provided that if R10 is naphthyl, v is 0, and each xe2x80x94WYxe2x80x94 is xe2x80x94C(O)NR7xe2x80x94 or xe2x80x94NR7C(O)xe2x80x94, then (i) Z is not xe2x80x94SO2OH; and (ii) if R1 or R2 is xe2x80x94C(O)NR4R5, then R13 is neither aryl nor substituted aryl. Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and these compounds of the invention as active ingredients are provided in still another aspect of the invention.